The ULT1, ULT2 and ULT3-programmes
ULT1, ULT2 and ULT3 are Ultupharma’s current antibiotics programmes. Antibiotics in these programmes have activity against a wide range of bacterial pathogens in the WHO and CDC priority lists (Table 1, click table to enlarge), including carbapenem resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. The ULT3 peptides have also activity against colistin resistant Escherichia coli, A. baumannii and Klebsiella pneumoniae. A confidential presentation is available describing these programmes.
The ULT1-programme is based on new antibacterial compounds discovered in cultures of Gram-negative soil bacteria, which have shown potent effect against Staphylococcus aureus strains MRSA, MRSE, MSSE, MSSA and VRE and strains resistant to mupirocin, vancomycin, etc. (Bjerketorp et al, J. Nat. Prod., 2017, 80, 2997-3002).
Patents have been granted in Sweden (SE539512) and in the US (US10471043 and US10933048). Several active analogues have been synthesized and more are planned.
A deep knowledge in nucleoside chemistry and biochemistry has resulted in the ULT2-programme containing several treatments active against a large number of multi-resistant Gram-negative and Gram-positive bacteria such as A. baumannii, E. coli, K. pneumoniae, K. oxytoca, Enterobacter cloacae, E. aerogenes, Serratia marcescens, P. aeruginosa, Proteus mirabilis, Salmonella typhimurium, Shigella sonnei, S. flexneri, Helicobacter pylori, Yersinia pestis, Haemophilus influenza, S. aureus, S. epidermis, Streptococcus pneumoniae, Micrococcus luteus, and Bacillus anthracis (Table 2, click table to enlarge).
ULT2A treatments give potent antibacterial effects in mice with peritonitis/sepsis and urinary tract E. coli infections, with no toxicity and at doses expected to be safe in humans. Further development is ongoing, targeting both Gram-negative and Gram-positive bacterial infections not responding to treatment with present antibiotics on the market. The therapeutic effects of ULT2 combinations are expected to be more than ten time more potent in humans than in mice as mice have exceptionally high thymidine concentrations counteracting the effect of ULT2 combinations. Humans have very low thymidine levels. An interesting possibility for ULT2C is topical use against skin infections. This has the advantage of obtaining inhibitory concentrations at the site of infection without risk for systemic toxicity and effect on the normal bacterial flora at other sites. ULT2C has potent effect against S. aureus resistant to many antibiotics such as methicillin and mupirosin and resistance to these antibiotics is increasing and a serious problem for patients with diabetic foot infections.
Patents have been granted in Sweden (SE540411), the US (US10828316 and US10828317), Japan (JP6895435), Europe (EP/NL/IE/GB/FR/DE/CH/BE3407898), Hong Kong (HK40046560A), China (CN201780004884.X), and Australia (AU2017212224). A national application has been filed in Canada (PCT/SE2017/050071).
The ongoing analysis of metabolites from microorganisms is efficiently resulting in a rapidly growing number of new compounds with promising antibiotic properties. New ways to isolate bacteria producing novel antibiotic compounds have also been developed by Ultupharma in collaboration with the research group at SLU, as described in the recent key-publication in Frontiers in Microbiology: Selective isolation of multidrug-resistant Pedobacter spp., producers of novel antibacterial peptides. One result from these developments is the ULT3-programme, which is a series of bacterial peptides with potent activity against Gram-negative bacteria, including carbapenem-resistant E. coli, A. baumannii and P. aeruginosa, and colistin resistant E. coli, A. baumannii and K. pneumoniae, along with acceptable toxicity and haemolysis properties. These antibiotic peptides are described in a recent publication in ACS Chemical Biology: Isopedopeptins A–H: Cationic Cyclic Lipodepsipeptides from Pedobacter cryoconitis UP508 Targeting WHO Top-Priority Carbapenem-Resistant Bacteria. ULT3 (isopedopeptin B) at sub MIC concentrations can reactivate old antibiotics with resisance problems, indlucing resistance to colistin. A local application of ULT3 in combination with systemic use of old antibiotics offers an interesting possibility to use in surgery.
A patent has been granted in Sweden (SE543054), and national applications have been filed in the US, South Africa, South Korea, Japan, Australia, Canada, China and Europe (PCT/SE2019/050789).